Reduced levels of neurotransmitters including acetylcholine occur in dementias of the Alzheimer type. In particular, a deficit in acetylcholine-mediated transmission is thought to contribute to the cognitive and neurobehavioral abnormalities associated with these disorders. Accordingly, drugs known to augment cholinergic transmission in the CNS are the mainstay of current therapy. Other diseases of the nervous system also involve decreased cholinergic transmission and are referred to as “hypocholinergic syndromes and disorders of the Central Nervous System (CNS)”. In addition to AD, and AD-type dementia, such diseases, herein below referred to as “hypocholinergic disorders” also include, but are not limited to, Alzheimer's Disease (AD), AD-type dementia, Progressive Supranuclear Palsy (PSP), Mild Cognitive Impairment (MCI), Lewy Body Disease dementia (LBD), Parkinson disease dementia (PDD), post-stroke dementia, vascular dementia, Traumatic Brain Injury (TBI), Senile dementia, Autism, Anorexia Nervosa, falls, post-operative delirium, Down syndrome, Tourette syndrome, tardive dyskinesia, Frontotemporal lobe dementia (FTD), Frontotemporal lobar degeneration, Pick's disease, Huntington's disease, Friedrich's ataxia, chronic neuropathic pain, schizophrenia, Cognitive Impairment associated with Multiple Sclerosis, and other disorders of the nervous system involving a deficit in acetyl-choline neurotransmission. It is well documented that schizophrenic patients experience cognitive disturbances that are not well addressed by current medications (reviewed in Foster et al, 2014).
MCRAs have been reported to dose-dependently improve the cognitive disturbances associated with schizophrenia, but the effect of MCRAs is of limited size and dose-dependent side effects prevent further increases in the MCRA doses.
Acetylcholinesterase inhibitors (AChEIs) are now not only part of the standard of care for patients suffering from a dementia of the Alzheimer type, but are also widely used off-label for various other chronic often progressive hypocholinergic disorders of the nervous system. As a general mechanism of action, AChEIs enhance acetylcholine-mediated neurotransmission. All act in the human CNS to increase and prolong the availability of acetylcholine by inhibiting its degradatory enzyme acetylcholinesterase (AChE). Four AChEIs have been approved by the U.S. FDA for the treatment of dementias of the Alzheimer type: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] and galantamine [Razadyne®]. Rivastigmine has also been approved for the treatment of Parkinson's disease dementia. AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
Unfortunately, however, none of the available AChEIs offers more than modest clinical benefit for patients suffering from any of the aforementioned dementing disorders, as traditionally administered, even when these medications are administered at their maximum safe and tolerated doses. This is the first problem limiting the success of AChEI therapy of Alzheimer type dementias.
A second problem limiting the success of current AChEI therapy of Alzheimer type dementias is that, even at recommended amounts, AChEIs produce dose limiting adverse reactions, mainly if not exclusively, by over-stimulating peripheral cholinergic receptors of the muscarinic type. As a result, signs and symptoms of untoward gastrointestinal, pulmonary, cardiovascular, urinary, and other systems dysfunction occur. These side effects commonly include, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss; increased bronchial secretions, dyspnea, bronchoconstriction and bronchospasm; bradycardia, supraventricular cardiac conduction abnormalities, vasodilation, hypotension, dizziness and syncope; urinary bladder spasm, increased urinary frequency, and incontinence; flushing and diaphoresis; fatigue, headache, lacrymation, miosis, and loss of binocular vision (Physicians' Desk Reference 2008, Thomson PDR, Montvale, N.J.).
Use of AChEIs with a nsPAChA (U.S. Pat. No. 8,404,701, the disclosure of which is incorporated herein by reference in its entirety) or with a non-anticholinergic antiemetic agent has been described (U.S. Pat. No. 8,877,768, the disclosure of which is incorporated herein by reference in its entirety).
Another way to increase the cholinergic transmission in the brain is to stimulate post-synaptic cholinergic receptors by administering an agonist of the muscarinic receptors, but the results were generally disappointing.
In fact, many MCRAs have been studied in the last two decades but, except for cevimeline (EVOXAC®), which is marketed in the U.S.A. for the limited indication of the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome, none of the MCRAs showed a significant activity on the CNS which could be used for the treatment of Alzheimer type dementia or of hypocholinergic disorders.
In a primate study, the muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (BuTAC) exhibited high affinity for muscarinic receptors, but induced vomiting that was mitigated by administration of domperidone (M. B. Andersen et al. Neuropsychopharmacology 2003; 28:1168-1175). No trial in humans with this muscarinc agonist apparently followed this study.
The (E)-N-methoxy-1-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)methanimine, a non-selective muscarinic acetylcholine receptor partial agonist with cognition-acting properties known as milameline and described in U.S. Pat. No. 6,037,347, the disclosure of which is incorporated herein by reference in its entirety, was investigated for the treatment of Alzheimer's disease. However, the drug, while possessing a pharmacological profile consistent with that of a muscarinic partial agonist, produced central cholinergic action in rats and monkeys at doses slightly higher than those stimulating peripheral cholinergic receptors (Schwarz R D, Callahan M J, Coughenour L L, Dickerson M R, Kinsora J J, Lipinski W J, Raby C A, Spencer C J, Tecle: “Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization”; J Pharmacol Exp Ther. 1999 November; 291(2):812-22—Schwarz 1999, the disclosure of which is incorporated herein by reference in its entirety). The development of milameline seems to be discontinued.
Similarly, the (3R)—N-methoxyquinuclidine-3-carboximidoyl cyanide hydrochloride known as sabcomeline and described in U.S. Pat. No. 5,278,170, the disclosure of which is incorporated herein by reference in its entirety, is a selective M1 receptor partial agonist that was under development for the treatment of Alzheimer's disease (Loudon J M, Bromidge S M, Brown F, et al.: “SB 202026: a novel muscarinic partial agonist with functional selectivity for M1 receptors”; J Pharmacol Exp Ther. 1997 December; 283(3):1059-68—Louden 1997, the disclosure of which is incorporated herein by reference in its entirety). It was submitted to phase III clinical trials before being discontinued (R & D Focus Drug News, Mar. 8, 2004).
Another MCRA, the 5-[4-(hexylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine, known as tazomeline and described in U.S. Pat. No. 5,041,455, the disclosure of which is incorporated herein by reference in its entirety, acts as a non-selective muscarinic acetylcholine receptor agonist. It was in clinical trials for the treatment of cognitive dysfunction such as that seen in Alzheimer's disease and schizophrenia, but, according to Wikipedia (Sep. 9, 2015), its “development was apparently scrapped for unknown reasons” and no sign of an effective development is known.
A close analog of tazomeline, the 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methyl-5,6-dihydro-2H-pyridine known as xanomeline and described in U.S. Pat. No. 5,043,345, the disclosure of which is incorporated herein by reference in its entirety, has been disclosed as a muscarinic acetylcholine receptor agonist with reasonable selectivity for the M1 and M4 subtypes. The efficacy of xanomeline, which stimulates muscarinic receptors in the brain and in the periphery was studied in patients with Alzheimer disease in a 6-month double-blind, placebo-controlled, parallel group trial. Compared to placebo, xanomeline was shown to significantly improve cognitive and behavioral symptoms of Alzheimer disease (Bodick et al, 1997; Shekhar et al, 2008), but also caused dose-dependent unacceptable side effects, including bradycardia, gastro-intestinal distress, excessive salivation, and sweating. Such side effects prevented the use of doses of xanomeline that could achieve maximum anti-dementia efficacy and reflect stimulation of cholinergic receptors outside the brain.
Xanomeline is also described in a transdermally administrable form in U.S. Pat. No. 5,980,933, the disclosure of which is incorporated herein by reference in its entirety, and a clinical experimentation of said preparation was announced. The paper Mirza, N. et al., CNS Drug Review, 9(2): 159-186 (2003) confirmed a phase II clinical trial with transdermal xanomeline, but no specific result appeared in the literature after that date.
A xanomeline fluorinated analog, the 3-[3-(3-(3-fluorophenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine oxalate, known as EUK 1001, was disclosed by Xiaoping Lei in CN1821243B and considered a promising therapeutic agent for the treatment of AD and age-related memory disorders (Yihui Cui, Dong Wang, Wen Si, Wen Lv, Yan Niu, Xiaoping Lei, Yinhe Hu and Xiaohua Cao: “Enhancement of memory function in aged mice by a novel derivative of xanomeline”; Cell Research; 2008; 18:1151-1153 published online 21 Oct. 2008—Yihui Cui 2008 the disclosure of which is incorporated herein by reference in its entirety). However, no result of clinical trials in human being using EUK1001 has been reported in the literature.
Dose-limiting adverse events attending the use of drugs that stimulate cholinergic transmission, such as xanomeline, appear to primarily reflect the excessive stimulation of peripheral cholinergic receptors, especially those of the muscarinic type (mAChRs), such that in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for xanomeline; in the patient population this led to a discontinuation rate higher than 50% while the effects on cognition were not robust and mainly seen at the highest doses tested (Mirza2003).
As a matter of fact, for the MCRAs tested in clinical trials for the treatment of Alzheimer disease,                the milameline maximum tolerated dose was determined as being 2 mg four times per day (J. J. Sramek et al. Life Sciences 1998, 62/3: 195-202);        the xanomeline minimum intolerated dose was reached at 115 mg three times a day, and 100 mg three times a day was defined as the MTD by J. J. Sramek et al. (J Clin Pharmacol 1995; 35:800-806), who also observed that higher xanomeline concentrations appear to be associated with reduced tolerance to the drug; the literature also shows that, in a 6-month double-blind, placebo-controlled, parallel group efficacy study, 59% of patients discontinued treatment after receiving 75 mg xanomeline orally three times daily, mainly because of adverse events, predominantly gastrointestinal (N. R. Mirza et al. CNS Drug Reviews Vol. 9, No. 2, pp. 159-186, 2003).        
In conclusion, the development of all of the above MCRAs was discontinued because the results of the studies were disappointing not due to a basic muscarinic inactivity of the products but because said products had limited efficacy at doses that were tolerable in patients, and induced dose-limiting, intolerable adverse effects at higher doses.
In a review published in NEUROLOGY, 49, July 1997, by H. Robert Brashear, MD, of the book “Muscarinic Agonists and the Treatment of Alzheimer Disease” (Edited by Abraham Fisher—R. G. Landes, 1996), the reviewer concluded his comment as follows: “It will be of interest to most clinicians who treat Alzheimer's disease and valuable to chemical researchers, basic neuroscientists, biochemists, and pharmacologists investigating cholinergic dysfunction and therapy”. Despite this clear interest and the extensive studies made on a series of compounds during the last two decades, none of the studied compounds became a drug for the treatment this disease for the reasons set forth above.
In addition, MCRAs consisting of allosteric modulators of the M1-muscarinic acetylcholine receptor are extensively studied and are the object of copious patent and scientific literature.
A review by B. J. Melancon, J. C Tarr, J. D. Panarese, M. R. Wood and C. W. Lindsley published in Drug Discovery Today; Volume 18, Numbers 23/24, December 2013, “Allosteric modulation of the M1 muscarinic receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease” (Melancon et al.), the disclosure of which is incorporated herein by reference in its entirety, illustrates the role of the M1 receptor in Alzheimer's disease and in schizophrenia by referring to selected allosteric modulators of the M1 receptor.
This review also reports that positive allosteric modulator MK-7622 entered Phase II clinical trials as an adjunct therapy to AChEIs in patients with AD. This positive allosteric modulator of the M1 receptor, 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, is described in U.S. Pat. No. 8,883,810, the disclosure of which is incorporated herein by reference in its entirety.
The precise causes of vomiting and related gastrointestinal symptoms induced bycholinergic therapy are not known. Presumably, these symptoms reflect cholinergic receptor hyperstimulation attending the administration of muscarinic agonists or of AChEIs.
An improvement in the treatment of Alzheimer type dementia is attained by a combined therapy associating a non-selective, peripheral anticholinergic agent, at a dose of from 20% to 200% the current daily doses, with an AChEI, at a dose up to about 6 times the maximal recommended dose of said AChEI, as disclosed in U.S. Pat. No. 8,404,701, the disclosure of which is herein incorporated by reference in its entirety. By such a treatment, a higher acetylcholinesterase inhibition in the CNS is achieved and greater relief of the symptoms of Alzheimer type dementia is enabled. This result was obtained by successfully inferring that the good dose-response obtained with the AChEIs, i.e. with enzyme inhibitors, would allow an increase of the inhibition of AChE in the CNS with a safe increase of the AChEI dose. Conversely, in the case of the muscarinic receptors, nothing in the literature suggests how to effectively take advantage of the properties of MCRAs. In particular, the literature does not give any indication or suggestion for exploiting the potentiality of said muscarinic agonists in the treatment of disease.
U.S. Pat. No. 8,877,768, the disclosure of which is herein incorporated by reference in its entirety, discloses a combined therapy associating a non-anticholinergic-antiemetic agent, at a dose of from 50% to 300% the current IR daily doses, with an AChEI, at a dose up to 4 times the maximal recommended doses of said AChEI when administered alone. However, the antiemetics, which are non-anticholinergic by definition, do not interfere with both the central and peripheral therapeutic activity of the AChEIs.
U.S. Pat. No. 8,883,810 (see also WO 2010/059773), the contents of which are incorporated herein in their entirety for reference, describing MK-7622, cites the combination of a class of aryl methyl benzoquinazolinone compounds disclosed therein with other drugs to render the administration safer or more effective or to reduce the risk of side effects or toxicity of said aryl methyl benzoquinazolinones. These combinations include anticholinergic drugs but the document does not disclose any non-selective, peripheral anticholinergic drug. On the contrary, it specifically cites biperiden and trihexyphenidyl hydrochloride as anticholinergics, both being central anticholinergic agents for the treatment of the Parkinson's disease. Centrally acting anticholinergics would block the beneficial effects of MCRAs on hypocholinergic disorders of the brain.
Similarly, U.S. Pat. No. 8,853,219, the contents of which are incorporated herein in their entirety for reference, discloses chemical compounds as muscarinic agonists that can be used to treat normal cognitive impairment that accompanies aging, or to treat disorders such as Alzheimer's disease, dementia, autism and schizophrenia; and also discloses their combination with any anticholinergic agent, including those that cross the Blood Brain Barrier (BBB) and also those that, as taught by WO 2009/120277 in the case of the AChEIs, do not cross the BBB.
However, the problem of dose-limiting adverse effects encountered during the clinical trials involving MCRAs, which can be expected to occur with any muscarinic receptor agonist remains unsolved.